ADCLEC.syn1 CAR T-Cell Therapy for Acute Myeloid Leukemia

Recruiting at 6 trial locations

Overseen By Mark Geyer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Steroids, Chemotherapy

Disqualifiers: Acute promyelocytic leukemia, CNS disease, Cardiovascular disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 2-7 days post-chemotherapy

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ADCLEC.syn1 CAR T cells for individuals with acute myeloid leukemia (AML) that has returned or hasn't responded to other treatments. The main goal is to find a safe dose that causes only mild side effects and then assess if this dose can effectively treat AML. The trial involves gradually increasing the dose given to participants to determine the optimal amount. Suitable candidates for this trial are those with AML who have tried other treatments without success and have a suitable stem cell donor identified for potential future needs. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participation. Steroids above a certain dose must be stopped 7 days before a procedure, and chemotherapy should be stopped one week prior. Hydroxyurea can be used up to 72 hours before certain procedures.

Is there any evidence suggesting that ADCLEC.syn1 CAR T cells are likely to be safe for humans?

Research shows that ADCLEC.syn1 CAR T-cell therapy is being tested for safety in people with acute myeloid leukemia (AML). Previous studies suggest that this treatment can be well-tolerated in similar situations, but monitoring for side effects remains crucial. In these studies, researchers aim to find the right dose that causes only mild or manageable side effects.

As an early-stage trial, the primary goal is to understand the treatment's safety and the body's reaction. The treatment undergoes close monitoring to ensure safety for participants. While the study of this treatment is encouraging, further research is necessary to confirm its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for AML?

Unlike the standard treatments for acute myeloid leukemia, which often rely on chemotherapy and stem cell transplants, ADCLEC.syn1 CAR T-cell therapy uses genetically engineered T cells to specifically target cancer cells. This approach works by modifying a patient's own immune cells to recognize and attack leukemia cells more effectively. Researchers are excited because this therapy has the potential to offer a more targeted attack on cancer cells with fewer side effects compared to traditional treatments. Additionally, the use of escalating doses in the trial aims to determine the most effective and safe amount, potentially leading to better outcomes for patients.

What evidence suggests that ADCLEC.syn1 CAR T cells might be an effective treatment for acute myeloid leukemia?

Research has shown that ADCLEC.syn1 CAR T cells, which participants in this trial will receive, hold promise for treating acute myeloid leukemia (AML). These cells effectively locate and destroy AML cells, even in challenging situations where other treatments might fail. In lab tests, ADCLEC.syn1 outperformed similar treatments by preventing cancer cells from escaping and regrowing. This suggests it could be a viable option for patients whose AML has returned or hasn't responded to standard treatments. Overall, early evidence indicates that ADCLEC.syn1 CAR T cells could effectively combat AML. ^{1 2 3 6 7}

Who Is on the Research Team?

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with relapsed or refractory Acute Myeloid Leukemia (AML) who are in good physical condition (ECOG 0-1), have a suitable stem cell donor, and functioning major organs can join this trial. Those with acute promyelocytic leukemia, certain infections like HBV/HCV, other active cancers needing treatment, recent heart issues, uncontrolled infections or previous CAR therapy cannot participate.

Inclusion Criteria

My kidney and liver functions are within the required limits.

I have a matching donor for a stem cell transplant.

I am fully active or can carry out light work.

Exclusion Criteria

I have not taken clofarabine or cladribine in the last 3 months.

I have been diagnosed with acute promyelocytic leukemia.

Oxygen saturation <90% on room air

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Chemotherapy

Participants receive conditioning chemotherapy prior to CAR T cell infusion

1 week

Inpatient or outpatient

Treatment

Participants receive ADCLEC.syn1 CAR T cell infusions with dose escalation to determine the maximum tolerated dose

2-7 days post-chemotherapy

Inpatient

Dose Expansion

Selected dose levels are tested in additional patients to determine the recommended phase 2 dose (RP2D)

Variable, up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ADCLEC.syn1 CAR T cells
• Conditioning chemotherapy

Trial Overview

The study is testing the safety of ADCLEC.syn1 CAR T cells along with conditioning chemotherapy in AML patients. It aims to find the highest dose that's safe with few side effects and then test its effectiveness against AML that has come back or hasn't responded to other treatments.

How Is the Trial Designed?

Group I: ADCLEC.syn1 CAR T cells Experimental Treatment 2 Interventions

The dose escalation cohort size of 3 patients in each cohort will be infused with escalating doses of ADCLEC.syn1 CAR T cells to inform the RP2D. There are 4 planned flat-dose levels: 25 × 10\^6, 75 × 10\^6 , 225 × 10\^6 , and 450 × 10\^6 CAR T cells and 1 de-escalation dose: 10 × 10\^6 CAR T cells. After dose escalation, one or two dose levels will be selected for dose expansion cohort(s).Two to 7 days following completion of the conditioning chemotherapy, the frozen CAR T cells will be thawed and administered. Conditioning chemotherapy may occur either outpatient or inpatient, and T cell infusions will occur as inpatient. Up to approximately 12 additional patients each if two doses are selected or approximately 16 additional patients, if one dose is selected, will be treated in the dose expansion phase to determine RP2D.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Published Research Related to This Trial

The study introduces a novel Fab-based adapter CAR (AdCAR) T-cell platform that allows for flexible targeting of acute myeloid leukemia (AML) cells, demonstrating effective cytotoxicity against AML cell lines and primary AML cells using various adapter molecules.

The AdCAR platform also shows promise in overcoming T-cell exhaustion by incorporating treatment-free intervals, which could enhance the effectiveness of CAR T-cell therapy in AML patients who face challenges like target antigen heterogeneity and T-cell dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML. Nixdorf, D., Sponheimer, M., Berghammer, D., et al.[2023]

Relapse after conventional chemotherapy is a significant issue in patients with acute myeloid leukemia (AML), and the only potentially curative treatment is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which can eliminate residual leukemia cells but still faces challenges with relapse.

Current efforts are focused on adapting CD19-targeted CAR T cell therapy, which has been successful in B-cell malignancies, for myeloid malignancies, but the lack of specific antigens on myeloid cells poses a risk of damaging normal blood stem cells, making it crucial to develop safe genetic modifications and strategies for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells for Acute Myeloid Leukemia: State of the Art and Future Directions. Mardiana, S., Gill, S.[2023]

The study presents a novel CD70-targeted CAR T cell therapy for acute myeloid leukemia, utilizing a multimodal approach that combines modifications to the CAR T cell construct with strategies to enhance the expression of leukemia antigens.

This synergistic strategy aims to improve the functionality of CAR T cells, potentially leading to more effective treatments for patients with acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD70 CAR T cells in AML: Form follows function. Mirazee, J., Shah, NN.[2022]

Cytokine release syndrome (CRS) is the most common adverse reaction reported after CAR-T therapy, with significantly higher reports for axicabtagene ciloleucel compared to tisagenlecleucel, indicating a need for careful monitoring of this side effect.

The study analyzed 1426 reports of adverse drug reactions from real clinical settings, supporting the overall safety profile of CAR-T therapies while confirming CRS as a major concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. Bonaldo, G., Montanaro, N., AlbertoVaccheri, ., et al.[2021]

A novel CAR therapy targeting both ADGRE2 and CLEC12A has been developed to effectively eliminate acute myeloid leukemia (AML) cells while minimizing damage to normal hematopoietic stem/progenitor cells, demonstrating a promising therapeutic window.

This dual-targeting strategy not only outperformed traditional CAR therapies in preclinical models but also showed similar off-target toxicity to existing treatments, suggesting a safer approach to AML treatment without the need for hematopoietic rescue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cooperative CAR targeting to selectively eliminate AML and minimize escape. Haubner, S., Mansilla-Soto, J., Nataraj, S., et al.[2023]

Chimeric antigen receptor (CAR) T cells targeting both CD123 and CD33, in addition to CLL-1, showed improved anti-tumor activity against acute myeloid leukemia (AML) cells, especially when the target cells expressed low levels of these antigens.

The study demonstrated that dual targeting led to enhanced T cell activation and better tumor control in vivo, resulting in improved survival rates in animal models without any antigen escape in residual tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy. Atilla, PA., McKenna, MK., Watanabe, N., et al.[2023]

CAR T-cell therapy for acute myeloid leukemia (AML) faces challenges due to the lack of specific surface antigens, but advancements are being made to improve its effectiveness.

Potential strategies to enhance the safety and efficacy of CAR T-cell therapy for AML include reducing the potency of CAR T cells, using transient CAR T cells during pre-transplant conditioning, and employing gene-edited allogeneic stem cell transplants to support sustained anti-AML activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How close are we to CAR T-cell therapy for AML? Gill, SI.[2021]

Current treatments for acute myeloid leukemia (AML) often fail or lead to relapses, highlighting the need for new therapeutic strategies.

Chimeric antigen receptor (CAR) T cell therapy, which has shown success in treating B-lineage cancers, is being explored for AML, with ongoing research into potential surface markers and strategies to improve its effectiveness in this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia. Fan, M., Li, M., Gao, L., et al.[2021]

CAR T-cell therapy shows promise in improving outcomes for patients with acute myeloid leukemia (AML), a condition with historically poor prognosis.

A significant challenge for the effectiveness of CAR T-cell therapy in AML is the identification of specific target antigens on leukemia cells, as well as the risk of immune escape due to changes in these antigens and a suppressive tumor environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. Sauer, T., Rooney, CM.[2020]

Up to 30% of patients with acute myeloid leukemia (AML) show some response to CAR T-cell therapy, but these responses are often not deep or long-lasting, indicating a need for improved treatment strategies.

Common targets for CAR T-cells in AML include CD123, CD33, and CLL-1, but while these therapies can lead to myeloablation and cytokine release syndrome, they rarely cause neurotoxicity, suggesting a relatively safe profile for certain side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. Cummins, K., Gill, S.[2023]

CAR T-cell therapy has the potential to improve outcomes for patients with acute myeloid leukemia (AML) by specifically targeting leukemia cells, but there are significant challenges to its effectiveness and safety.

Strategies being explored to enhance CAR T-cell therapy in AML include targeting specific leukemia antigens to reduce side effects, using checkpoint inhibitors to counteract immune suppression caused by leukemia, and developing allogenic CAR T cells to make the treatment more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospect of CAR T-cell therapy in acute myeloid leukemia. Badar, T., Manna, A., Gadd, ME., et al.[2022]

Citations

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The purpose of this study is to test the safety of ADCLEC.syn1 CAR T cells in people with relapsed or refractory AML. The researchers will try to find the ...

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This phase I trial tests the safety, side effects, and best dose of ADCLEC.syn1 chimeric antigen receptor (CAR) T-cells in treating patients with acute myeloid ...

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pmc.ncbi.nlm.nih.gov/articles/PMC10428506/

S104: DIFFERENTIAL TARGET PROFILES AND ...

We next compared the anti-leukemic efficacy of ADCLEC.syn1 vs a reference CD33-CAR in AML xenograft models of different AML engraftment patterns and additional ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S1535610823003264

Cooperative CAR targeting to selectively eliminate AML ...

ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis ...

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ecancer.org

ecancer.org/en/video/11354-adclec-syn1-and-cd33-cars-in-humanised-acute-myeloid-leukaemia-models-shows-promising-efficacy

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The results showed ADCLEC.syn1 demonstrated high levels of efficacy across a range of densities in humanised acute myeloid leukaemia models.

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mskcc.org/cancer-care/clinical-trials/23-002

A Phase 1 Study of ADCLEC.syn1 CAR T Cell Therapy in ...

Researchers want to find the best dose of ADCLEC.syn1 that can be used in people with leukemia. The people in this study have acute myeloid leukemia (AML)

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connect.careboxhealth.com/en-US/trial/listing/391573

A Study of ADCLEC.syn1 in People With Acute Myeloid ...

The purpose of this study is to test the safety of ADCLEC.syn1 CAR T cells in people with relapsed or refractory AML. The researchers will try to find the ...